The present invention provides new triazolo[4,5-d]pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation.
Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re-occlusion.
A number of converging pathways lead to platelet aggregation. Whatever the initial stimulus, the final common event is a cross-linking of platelets by binding of fibrinogen to a membrane-binding site, glycoprotein IIb/IIIa (GPIIb/IIIa). The high anti-platelet efficacy of antibodies or antagonists for GPIIb/IIIa is explained by their interference with this final common event. However, this efficacy may also explain the bleeding problems that have been observed with this class of agent. Thrombin can produce platelet aggregation largely independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms. Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again may produce excessive bleeding because they function as both anti-platelet and anti-coagulant agents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp. 1638-1642).
It has been found that adenosine 5xe2x80x2-diphosphate (ADP) acts as a key mediator of thrombosis. A pivotal role for ADP is supported by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT, serotonin) will only produce aggregation in the presence of ADP. The limited anti-thrombotic efficacy of aspirin may reflect the fact that it blocks only one source of ADP which is that released in a thromboxane-dependent manner following platelet adhesion (see e.g. Antiplatelet Trialists"" Collaboration (1994), Br. Med. J. 308, pp. 81-106 and Antiplatelet Trialists"" Collaboration (1994), Br. Med. J. 308, pp. 159-168). Aspirin has no effect on aggregation produced by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow.
ADP-induced platelet aggregation is mediated by the P2T receptor subtype located on the platelet membrane. The P2T receptor (also known as P2YADP or P2TAC) is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor which is as yet uncloned. The pharmacological characteristics of this receptor have been described, for example, in the references by Humphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and Fagura et al., Br. J. Pharmacology (1998) 124, 157-164. Recently it has been shown that antagonists at this receptor offer significant improvements over other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213). Accordingly there is a need to find further P2T (P2YADP or P2TAC) antagonists as anti-thrombotic agents.
International Patent Application WO 9905143 discloses generically a series of triazolo[4,5-d]pyrimidine compounds having activity as P2T (P2YADP or P2TAC) antagonists. It has now been found that certain compounds within the scope of International Patent Application WO 9905143 but not specifically disclosed therein exhibit high potency combined with surprisingly high metabolic stability and bioavailibility, such that the predicted therapeutic dose for prolonged inhibition of aggregation in man shows advantage.
In a first aspect the invention therefore provides a compound of formula (I): 
wherein:
R1 is C3-5 alkyl optionally substituted by one or more halogen atoms;
R2 is a phenyl group, optionally substituted by one or more fluorine atoms;
R3 and R4 are both hydroxy;
R is XOH, where X is CH2, OCH2CH2 or a bond;
or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.
provided that:
when X is CH2 or a bond, R1 is not propyl.
when X is CH2 and R1 is CH2CH2CF3, butyl or pentyl, the phenyl group at R2 must be substituted by fluorine.
when X is OCH2CH2 and R1 is propyl, the phenyl group at R2 must be substituted by fluorine.
Alkyl groups, whether alone or as part of another group are straight chained and fully saturated.
Suitably R1 is a C3-5 alkyl optionally substituted by one or more fluorine atoms. Preferably R1 is C3-5 alkyl optionally substituted on the terminal carbon by three fluorine atoms. More preferably R1 is 3,3,3,-trifluoropropyl, butyl or propyl.
Suitably R2 is phenyl or phenyl substituted by one or more fluorine atoms. Preferably R2 is phenyl, 4-fluorophenyl or 3,4-difluorophenyl.
Suitably R is XOH where X is CH2, OCH2CH2 or a bond.
Preferably R is CH2OH or OCH2CH2OH.
Particularly preferred compounds include:
[1R-[1xcex1,2xcex1,3xcex2(1R*,2S*),5xcex2]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[1R-[1xcex1,2xcex1,3xcex2(1R*,2S*),5xcex2]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[1S-(1xcex1,2xcex1,3xcex2(1S*,2R*),5xcex2]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
[1R-[1xcex1,2xcex1,3xcex2(1R*,2S*),5xcex2]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
[1S-[1xcex1,2xcex2,3xcex2,4xcex1(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;
[1S-(1xcex1,2xcex1,3xcex2(1S*,2R*),5xcex2)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
[1S-[1xcex1,2xcex1,3xcex2,5xcex2(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol [1S-[1xcex1,2xcex2,3xcex2,4xcex1(1S*, 2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;
[1S-[1xcex1,2xcex1,3xcex2(1S*,2R*),5xcex2]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol;
and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises:
(a) reacting a compound of formula (II): 
where R, R1, R3 and R4 are as defined in formula (I), or are protected derivatives thereof, or R3 and R4 together form a bond in the 5-membered ring, or R is CH2CH2ORxe2x80x2, where R is C1-6 alkyl or benzyl, and L is a leaving group such as halogen or SR, with a compound of formula (III): 
where R2 is as defined in formula (I), or is a protected derivative thereof,
or where X is a bond:
(b) hydroxylation of a compound of formula (IV): 
where R1 is defined in formula (I) and R8 is H or CH2CH2OP3 where P3 is H or a protecting group or R8 is CH2COORxe2x80x2 where Rxe2x80x2 is C1-6 alkyl or benzyl, and Z is NH2 or 
where R2 is defined in formula (I).
and for both (a) and (b) optionally thereafter and in any order:
converting one or more functional groups into further functional groups;
removing any protecting groups;
forming a pharmaceutically acceptable salt or solvate, or a solvate of such a salt.
Compounds of formula (II) can be reacted with amines of formula (III) in the presence of a base, such as a tertiary organic amine, in an inert solvent, such as dichloromethane, at ambient or elevated temperature. Other suitable bases include inorganic bases such as potassium carbonate.
The hydroxy groups R3 and R4 can be protected as groups OP1 and OP2 where P1 and P2 are protecting groups. Examples of suitable protecting groups in compounds of formula (II) are C1-6 alkyl (preferably methyl), benzyl, (C1-6alkyl)3Si (preferably t-butyldimethylsilyl), and a C(O)C1-6alkyl group such as acetyl. Preferably the two groups P1 and P2 together with the atoms to which they are attached form an alkylidene ring such as a methylidene or isopropylidene ring. Alternatively P1 and P2 can form an alkoxymethylidene ring such as ethoxymethylidene.
Protecting groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J W F McOmie, Plenum Press (1973), and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Ester protecting groups can be removed by basic hydrolysis, for example by using a metal hydroxide, preferably an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxide in a solvent, such as aqueous ethanol or aqueous tetrahydrofuran, at a temperature of from 10xc2x0 to 100xc2x0 C., preferably the temperature is around room temperature; or by acidic hydrolysis using a mineral acid such as HCl or a strong organic acid such as trichloroacetic acid in a solvent such as aqueous 1,4-dioxane. Trialkylsilyl protecting groups can be removed by the use of, for example, a fluoride ion source, for example tetra-n-butylammonium fluoride or hydrogen fluoride. When one or both of P1 and are C1-6 alkyl, deprotection can be achieved using boron tribromide. Benzyl groups can be removed by hydrogenolysis using a transition metal catalyst, for example palladium on charcoal, under an atmosphere of hydrogen, at a pressure of from 1 to 5 bar, in a solvent, such as acetic acid.
A compound of formula (II) can be prepared by diazotising a compound of formula (V): 
wherein R1 is as defined in formula (I), and R is as defined in formula (I), or is a protected derivative thereof, or is OCH2CO2Rxe2x80x2, where Rxe2x80x2 is C1-6 alkyl or benzyl, and L is as defined above and R3 and R4 are as defined in formula (I) or are protected derivatives thereof or R3 and R4 together form a bond in the 5-membered ring, with a metal nitrite, for example an alkali metal nitrite, especially sodium nitrite in dilute aqueous acid, for example 2M HCl, or with a C1-6-alkyl nitrite, in an inert solvent, at a temperature of from about xe2x88x9220 to about 100xc2x0 C. Preferred conditions are isoamyl nitrite in acetonitrile at about 80xc2x0 C.
A compound of formula (V) wherein R is CH2OH, R3 and R4 are hydroxyl or protected derivatives thereof and L is as defined above, can be prepared by reducing a compound of formula (VI): 
wherein R1, L, P1 and P2 are as defined above.
The reduction of the nitro group can be carried out for example by using hydrogenation with a transition metal catalyst at a temperature around room temperature, for example palladium on charcoal under an atmosphere of hydrogen, preferably at a pressure from 1 to 5 atmospheres, in a solvent, for example ethanol, or by using iron in an acidic solvent such as acetic acid at a temperature of about 100xc2x0 C.
Reduction of the lactam can be carried out using complex metal hydrides such as lithium aluminium hydride in a solvent such as ether or preferably, by using sodium borohydride in a suitable solvent such as methanol.
A compound of formula (VI) can be prepared by reacting a compound of formula (VII): 
wherein L and R1 are as defined above and L1 is a leaving group, for example a halogen atom, wherein L and L1 are preferably the same, with a compound of formula (VIII): 
wherein P1 and P2 are as defined above, in the presence of a base such as C1-6-alkyl-M or MH wherein M is a metal ion, for example n-butyl lithium, in an inert solvent, such as tetrahydrofuran, at a temperature of from about xe2x88x9210 to about 100xc2x0 C. Preferably sodium hydride is used in tetrahydrofuran at room temperature.
One or more functional groups can be converted into further functional groups using standard chemistry. A compound where X is a bond can be converted to a compound where X is O(CH2)2 by treatment with base followed by LY where L is a leaving group and Y is (CH2)2OH or a protected version thereof or Y is CH2COORxe2x80x2 where Rxe2x80x2 is C1-6 alkyl or benzyl. A compound where R is CH2CH2OR may be converted into a compound where R is O(CH2)2OH by reduction, for example using DIBAL-H(copyright). The group SR1 can be interconverted by oxidation of the sulfur, for example using oxone(trademark) or mCBPA, followed by treatment with a compound R1xe2x80x2-SM where R1xe2x80x2 is a different R1 group and M is a metal such as sodium. Alternatively the product of the sulfur oxidation may be treated with MSH where M is a metal such as sodium, followed by treatment with a base and R1xe2x80x2X where R1xe2x80x2 is a different R1 group and X is a leaving group. Suitable bases include N,N-diisopropylethylamine.
A compound of formula (II) where R, R1, R3, and R4 are as defined in formula (I) or are protected derivatives thereof, or R3 and R4 together form a bond in the 5-membered ring, or R is OCH2CO2Rxe2x80x2 where Rxe2x80x2 is C1-6 alkyl or benzyl, and L is a leaving group such as halogen, may be converted into a compound of formula (II) where R, R1, R3, and R4 are defined above and L is NH2 by treatment with a diazotizing agent in the presence of a halogenating agent, preferably isoamyl-nitrite and carbon tetrabromide.
A compound of formula (II) where R, R1, R3, and R4 are defined above and L is NH2 may be prepared by treating a compound of formula (II) where R, R1, R3, and R4 are as defined above and L is a leaving group such as halogen, with ammonia in a solvent such as methanol.
Compounds of formula (V) can also be prepared by treating a compound of formula (XI) 
where R, R3 and R4 are as defined in formula (I) or are protected derivatives thereof or R is OCH2CO2Rxe2x80x2 where Rxe2x80x2 is C1-6 alkyl or benzyl, or R3 and R4 together form a bond in the 5-membered ring,
with a compound of formula (VII) as defined above, followed by reduction of the nitro group. The reaction is carried out in an inert solvent such as dichloromethane or 1,4-dioxane, in the presence of a non-nucleophilic base, such as N,N-diisopropylamine, at a tempeature of about xe2x88x9220xc2x0 C. to about 150xc2x0 C., preferably at ambient temperature.
Compounds of formula (II) where R is as defined in formula (I), R3 and R4 together form a bond in the 5-membered ring, and L is SR1, or a protected derivative thereof, can be prepared by reacting a compound of formula (XII): 
where R1 groups are as defined in formula (I), with a compound of formula (XIII): 
in which R7 is H or a protected derivative thereof. The reaction can be carried out in the presence of a suitable transition metal complex, preferably tetrakistriphenylphosphine palladium(0).
Compounds of formula (XII) can be prepared from compounds of formula (XIV): 
by reacting with a compound R1X where R1 is as defined in formula (I) and X is a leaving group such as halo, followed by cyclisation.
Compounds of formula (XI) where R is OH or a protected version thereof and R3 and R4 are as defined in formula (I) or are protected derivatives thereof may be prepared from compounds of formula (XIII) where R7 is H or a protecting group by treatment with a bisester of imidodicarbamic acid using palladium catalysis followed by hydroxylation of the double bond, and optionally, deprotection of the nitrogen. Preferably imidodicarbonic acid, bis-(1,1-dimethylethyl)ester and tetrakistriphenylphosphine palladium(0) are used followed by osmium tetroxide and deprotection using hydrochloric acid in methanol.
Compounds of formula (XI), where R is OCH2CO2Rxe2x80x2 where Rxe2x80x2 is C1-6 alkyl and R3 and R4 together form a bond in the 5-membered ring, may be formed from compounds of formula (XIII), where R7 is H or a protecting group, by treatment with an azide in the presence of a palladium catalyst, followed by reduction of the azide and alkylation of the alcohol as described previously.
Compounds of formula (XI) where R is OCH2CH2OH and R3 and R4 are as defined in formula (I) or are protected derivatives thereof may be prepared from compounds of formula (XI) where R is OH and R3 and R4 are as defined in formula (I) or are protected derivatives thereof, by protection of the nitrogen, alkylation of the alcohol using a 2-halo-acetic acid ester, followed by reduction of the ester and deprotection of the nitrogen. We prefer protection of the nitrogen as a carbobenzyloxy derivative using benzyl chloroformate followed by alkylation of the alcohol using ethyl bromoacetate and potassium t-butoxide, reduction of the ester using lithium borohydride in tetrahydrofuran and deprotection of the nitrogen by hydrogenation in the presence of palladium on carbon. In addition we prefer the case where the alcohols R3 and R4 are protected as an isopropylidene ring.
The amines of formula (III) can be prepared using procedures described in H Nishiyama et al, Bull. Chem. Soc., Jpn., 1995, 68, 1247, P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1, Amines and Related Compounds; Optical Resolution and Information Centre: Manhattan College, Riverdale, N.Y., 1978, p120, J. Vallgarda et al, J. Chem. Soc. Perkin 1, 1994, 461 or in International Patent Application WO 9905143.
All novel intermediates form a further aspect of the invention.
Salts of the compounds of formula (I) may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or a derivative thereof, with one or more equivalents of the appropriate base (for example ammonium hydroxide optionally substituted by C1-6-alkyl or an alkali metal or alkaline earth metal hydroxide) or acid (for example a hydrohalic (especially HCl), sulphuric, oxalic or phosphoric acid). The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. water, ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin. The non-toxic physiologically acceptable salts are preferred, although other salts may be useful, e.g. in isolating or purifying the product.
The compounds of the invention act as P2T (P2YADP or P2TAC) receptor antagonists. Accordingly, the compounds are useful in therapy, including combination therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, including coronary angioplasty (PTCA), endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome, thrombotic complications of septicaemia, adult respiratory distress syndrome, anti-phospholipid syndrome, heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venous thrombosis such as deep vein thrombosis, venoocclusive disease, haematological conditions such as myeloproliferative disease, including thrombocythaemia, sickle cell disease; or in the prevention of mechanically-induced platelet activation in vivo, such as cardiopulmonary bypass and extracorporeal membrane oxygenation (prevention of microthromboembolism), mechanically-induced platelet activation in vitro, such as use in the preservation of blood products, e.g. platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud""s phenomenon, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process. Further indications include treatment of CNS disorders and prevention of the growth and spread of tumours.
According to the invention there is further provided the use of a compound according to the invention as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of the above disorders. In particular the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and stable and unstable angina, especially unstable angina. The invention also provides a method of treatment or prevention of the above disorders which comprises administering to a person suffering from or susceptible to such a disorder a therapeutically effective amount of a compound according to the invention.
The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally.
The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers include sugars and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler(copyright) in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound with or without a carrier substance is delivered to the patient.
The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration.
For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved either in a readily volatile organic solvent or an aqueous solvent.
For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.